Open-minded scepticism: inferring the causal mechanisms of human ageing from genetic perturbations

Given the myriad of age-related changes and the many proposed mechanistic theories of ageing, a major problem in gerontology is distinguishing causes from effects. This review aims to identify and evaluate those mechanisms which have gathered experimental support in favour of seeing them as a cause rather than an effect of ageing. Recent results related to energy metabolism and ageing, the free radical and the DNA damage theories of ageing are reviewed and their predictions evaluated through a systems biology rationale. Crucial in this approach are genetic manipulations in animal models that enable researchers to discriminate causes from effects of ageing and focus on the causal structure of human ageing. Based on a system-level interpretation, the GH/IGF-1 axis appears the most likely explanation for caloric restriction and a possible causal mechanism of human ageing. Although much work remains to fully understand the human ageing process, there is little evidence that free radicals are a causal factor in mammalian ageing, though they may be involved in signalling pathways related to ageing. On the other hand, studying how the DNA machinery affects ageing appears a promising avenue for disclosing the human ageing process.